The Immune System in Mood Disorders: From Inflammation to Intervention

Mood disorders—including major depressive disorder and bipolar disorder—are increasingly recognized as conditions with significant immunological underpinnings. Elevated levels of pro-inflammatory cytokines (such as IL-1β, IL-6, and TNF-α), microglial activation, and disrupted blood–brain barrier integrity have been documented in patients with depressive and manic episodes, implicating neuroinflammation in both pathogenesis and symptom severity. This review synthesizes current evidence linking peripheral and central immune dysregulation to mood symptoms, highlighting key molecular pathways (e.g., the kynurenine pathway, Toll-like receptor signaling, and inflammasome activation) that bridge systemic inflammation to neurochemical and neuroendocrine changes. We further examine emerging interventions aimed at modulating these immune mechanisms, from adjunctive anti-cytokine therapies (monoclonal antibodies targeting TNF-α or IL-6) and small-molecule inhibitors of microglial activation, to repurposed agents with immunomodulatory properties (e.g., minocycline, celecoxib) and lifestyle approaches (exercise, dietary omega-3 fatty acids). Preclinical studies and early-phase clinical trials demonstrate that targeted immunotherapy can ameliorate depressive symptoms, normalize inflammatory biomarkers, and enhance treatment response when combined with standard antidepressant regimens. We discuss the challenges of patient stratification based on inflammatory profiles, potential risks of long-term immunosuppression, and the need for biomarkers to predict treatment efficacy.